Methamphetamine (METH) addiction currently presents an enormous public health issue, and yet no therapeutic agent is currently approved for its treatment. Psychostimulant addiction is a chronic, progressive disease driven by numerous persistent neurophysiological adaptations. METH self-administration increases input of the neuropeptide neurotensin onto dopamine (DA) neurons in the ventral tegmental area (VTA), which are extensively implicated in drug reward processes. While literature evidence and our preliminary results suggest that neurotensin decreases DA autoreceptor-mediated signaling, the role of DA D2 autoreceptors in drug self-administration has not been described. We have recently identified what had been a missing tool in the study of DA autoreceptors and DA-mediated synaptic transmission: an inhibitory postsynaptic current (or IPSC) mediated directly by dendrodendritic DA neurotransmission in the VTA. The identification of the DA IPSC allows us, for the first time, to directly address synaptic questions concerning the relationship between METH abuse and DA neurotransmission. The goal of this application is to determine key synaptic adaptations at the level of the DA cell body that are responsible for escalating METH self-administration. Our central hypothesis is that METH use decreases D2 autoreceptor signaling in VTA DA neurons through a neurotensin-dependent rise in intracellular calcium, producing an escalation of METH self-administration behavior. We will test this by combining patch clamp electrophysiology in brain slices with intravenous METH self-administration and VTA site-specific drug microinjections in mice. The studies in Aim 1 will determine the mechanisms responsible for long-term depression of the DA IPSC. The hypothesis to be tested is that that long term depression of DA IPSCs is produced by a neurotensin receptor-dependent rise in intracellular calcium producing the activation of protein phosphatase 3. The studies in Aim 2 will determine the changes in the DA IPSC produced by METH self-administration. The hypothesis to be tested is that in vivo contingent METH self-administration decreases autoreceptor signaling through a neurotensin-dependent mechanism. The studies in Aim 3 will determine the role of DA autoreceptor-mediated neurotransmission on the escalation of METH self-administration. The hypothesis to be tested is that autoreceptor signaling directly limits METH intake, and that neurotensin-induced depression of this signal contributes to the escalation of self-administration observed with prolonged access to the drug. The results of these studies will identify key cellular mechanisms responsible for decreased autoreceptor signaling, and will determine how this decrease in dendrodendritic DA neurotransmission produces escalation of METH self-administration. These findings will provide a detailed understanding of the relationship between neurotensin, DA neuron activity and METH self-administration and will lay the foundation for therapeutics targeting neurotensin- and autoreceptor-mediated signaling.